The present public health threat in diabetes mellitus and metabolic syndrome remains strongly linked to the epidemic of obesity in the US. At the pathophysiologic level, exciting studies from our group have been at the forefront in establishing circadian disruption as a novel risk factor for obesity and diabetes mellitus. Remarkably, animals provided a high-fat diet exhibit profound disruption in both molecular and behavioral circadian rhythms, and shiftwork and sleep loss has been associated with obesity and metabolic syndrome in humans, but our understanding of the mechanisms interconnecting circadian disruption with obesity and metabolic comorbidities remains in its infancy. The circadian system is organized hierarchically with brain pacemaker cells controlling metabolic cycles in peripheral cells. Recently, our genetic and genomic work has established an essential role of the molecular clock in the rhythmic regulation of hunger and peripheral glucose homeostasis through the control of NPY/AgRP neurons, revealing a requirement for the clock in energy sensing at the level of brain, and in turn, pinpointing brain clock pathologies as a factor in metabolic disease. Through stereotactic targeting, we find that clock gene ablation specifically within ?pacemaker? neurons causes profound obesity, due to abrogated signaling to major regions involved in the regulation of body weight, metabolism and thermogenesis. The forward-looking goal of this career development application is to apply physiological, genetic, and behavioral approaches to determine mechanisms through which circadian disruption contributes to obesity and diabetes, with a specific focus on how disruption of circadian-energy neuron neurocircuitry leads to hyperphagia, weight gain, peripheral insulin resistance, liver fat accumulation, and impaired glucose disposal in skeletal muscle. Building on an expert neuroscientific and metabolic collaborative network the approach is to utilize a combination of chemogenetic targeting to control activity of the clock-energy neuron circuit, thereby simulating the effect of jetlag and sleep disruption on whole-body metabolism. Molecular profiling will be utilized to identify circadian signals that control hunger neuron activity and peripheral glucose metabolism, and to develop behavioral and genetic interventions to reduce body weight in animal models of obesity. By first honing the above techniques, the proposed projects will enable the applicant to subsequently employ this unique set of approaches in the R00 phase, in clinically relevant models of weight loss and regain, to uncover the role of circadian rhythm disruption in successful long-term weight loss and as an intervention to increase insulin sensitivity and treat diabetes. As such, this work has direct translational implications for public health, for understanding how chronic disruption of the circadian system ? as experienced in shift work, jet lag and artificial light exposure at night ? may be implicated in the ongoing obesity epidemic. In summary, our proposed research will enable the applicant to become an independent principal investigator, and will be the first to elucidate mechanisms linking circadian disruption to metabolic disease through an integrated analysis combining studies in brain with peripheral tissues.